The Utility of Betahistine Dihydrochloride, a Structural Analog of Histamine, in Clozapine-associated Daytime Sedation: A Case Series

Clozapine is the drug of choice for the management of treatment-resistant schizophrenia. Excessive sedation (up to 70%) is one of the most common side effects of it. Although tolerance develops to some extent, 17%–67% of patients remain permanently affected. Factors associated with sedation include age, concomitant medications, total dose, timing, and the clozapine: norclozapine, plasma ratio, although an exact explanation is still not clear. The definite protocols are there for the management of some side effects (i.e., agranulocytosis), but other side effects like excessive sedation remain a challenge for the treating physicians.^{1, 2} The histaminergic tuberomammillary nucleus, located in the hypothalamus, plays a crucial role in the regulation of sleep–wake cycle. They fire during wakefulness and their activities are related to a high level of vigilance. In contrast, they cease firing and then remain quiescent during slow-wave sleep (SWS) and rapid eye movement (REM) sleep. ³ H1 and H3 receptors are involved in the regulation of sleep–wake cycle. Histamine or H1 receptor agonists lead to wakefulness, while H1 receptor antagonists lead to induction of sleep. The H3 receptor is an auto-receptor and modulates the synthesis and release of histamine. H3 receptor activation leads to decreased histamine release and induces sleep, while blockade of the H3 receptor causes wakefulness. ⁴

Betahistine dihydrochloride (N-methyl-N-β-[2-pyridyl] ethylamine-dihydrochloride) is a structural analog of histamine. This centrally acting H1 receptor agonist and H3 antagonist has been in use for the treatment of Meniere’s disease and vertigo since the early 1960s. Betahistine dihydrochloride and its metabolites lead to wakefulness by showing direct histamine-like actions, or by blocking H3 receptors, increasing the release of histamine and other neurotransmitters such as acetylcholine,noradrenalin, serotonin, gamma-aminobutyric acid, and dopamine.^{5, 6}

Here, we are discussing three cases of treatment-resistant schizophrenia experiencing excessive daytime sedation associated with clozapine and its management with betahistine dihydrochloride.

Case 1

Mr. A, a 46-year-old, married male, graduate, and clerk by occupation, presented with a total duration of illness of 14 years, continuous course, with no family history of any psychiatric illness. He was diagnosed with schizophrenia (as per ICD-10) due to his third-person auditory hallucinations, delusion of control, and significant socio-occupational dysfunction. The patient was already on 6 mg risperidone and 10 mg haloperidol for the last 3 years, 16 sessions of modified electroconvulsive therapy were also administered, and no major improvement was reported. Hence, after baseline investigations (i.e., complete blood count, random blood sugar, and ECG), clozapine was started, gradually titrated up to 400 mg/day in a divided dose (200 mg in the morning and 200 mg at night) within 16 weeks with substantial improvement in psychotic symptoms, the patient developed excessive daytime sedation. Subsequently, the dose was rescheduled to 100 mg in the morning and 300 mg at night; initially, there was mild improvement in daytime sedation, but again in a few days, the patient started complaining of excessive daytime sedation due to which the patient had difficulty in doing various day-to-day activities. The further patient was advised to take 400 mg of clozapine only at night. Still, there was no significant change in excessive daytime sedation was reported. Clozapine dose reduction was tried but resulted in deterioration in psychotic symptoms so the patient continued on the same dose of 400 mg/day at night. So, options such as the use of psycho stimulants or betahistine dihydrochloride and its risk/side effects profile were discussed with the patient and attendants. They agreed to a trial of betahistine dihydrochloride. Hence, it was added 8 mg/day in two divided dosages, morning and afternoon, with a gradual increase of 8 mg on every third day, and dose titration up to 48 mg/day was done in three divided dosages. After 2 weeks, a substantial improvement in excessive daytime sedation was reported on the visual analog alertness scale from sleepy to alert. In follow-up consultations over the next 2 months, he was found managing well with improvement in all the daytime activities.

Case 2

Mrs. B, a 25-year-old, unmarried female, with no family history of any psychiatric illness, diagnosed case of schizophrenia (as per ICD-10) in the last 2 years, was already on a 200 mg nighttime dose of clozapine for the last 6 months and was maintained well. She presented to us in an outpatient facility with a complaint of excessive daytime sleepiness only, causing severe hindrance in daily activities of living. The baseline investigations (i.e., random blood sugar, complete blood count, and ECG) were done and came out within normal limits. So, options such as reduction in the dose of clozapine, use of psycho stimulants or betahistine, and its risk/side effects profile were discussed with the patient and attendants. They agreed to a trial of betahistine dihydrochloride. Hence, it was added 8 mg/day in two divided dosages, with a gradual increase of 8 mg on every third day, and dose titration up to 32 mg/day was done in three divided dosages. After 8–10 days of adjunctive treatment, a substantial improvement in excessive daytime sedation was reported on the visual analog alertness scale from sleepy to alert. In follow-up consultations, over the next3 months, she was found managing well with improvement in daytime activities.

Case 3

Mr. C, a 29-year-old, married male, ex-army person, with no family history of any psychiatric illness had been followed-up for schizophrenia (as per ICD-10) for about 5 years with multiple trials of typical and atypical antipsychotics (olanzapine 20 mg, trifluoperazine 15 mg, and amisulpride 600 mg) for an adequate period. He was admitted to the ward with third-person auditory hallucinations and olfactory hallucinations (odd fragrance coming from him and surroundings). After a detailed workup and baseline investigations (i.e., complete blood count, random blood sugar, and ECG), clozapine (12.5 mg/day) was started and titration up to 300 mg/day was done within 4 weeks in two divided dosages. With the substantial improvement in psychotic symptoms, there was excessive daytime sleepiness. He spent most of the time in bed and was unable to maintain a daily routine. So, all the dose of clozapine was shifted to nighttime only, but still, excessive daytime sedation continued with only a minimal improvement. The clozapine dose reduction resulted in a deterioration in psychotic symptoms. So, options such as the use of psycho-stimulants or betahistine dihydrochloride and its side effects profile were discussed with the patient and attendants. They agreed to a trial of betahistine dihydrochloride. Hence, it was added 8 mg/day in two divided dosages, with a gradual increase of 8 mg on every third day, and dose titration up to 40 mg/day was done in three divided dosages. After 10 days, there was a substantial improvement in excessive daytime sedation was reported on the visual analog alertness scale from sleepy to alert. Thus, the patient was discharged from the hospital, and in follow-up consultations over the next 2 months, he was found to managing well with improvement in all the daytime activities.

Discussion

Psycho-stimulant drugs are recommended in addition to antipsychotic dose reduction, giving a larger part of the dose at bedtime and avoiding other sedating medications in order to counter the antipsychotic-induced sedation. ² In the above-mentioned cases, other options like clozapine dose reduction were tried but led to an increase in psychotic symptoms. The use of psycho-stimulants (e.g., modafinil) was denied by attendants/patients because of the risk of dependence as discussed with them. Hence, betahistine dihydrochloride was used in all the cases. In this case series, case A was on 400 mg/day of clozapine and required 48 mg/day of betahistine dihydrochloride to attain wakefulness, while case B was on 200 mg/day of clozapine and achieved wakefulness at 32 mg/day of betahistine dihydrochloride. Similarly, case C was on 300 mg/day and achieved wakefulness at 40 mg/day of betahistine dihydrochloride. From this case series, we can hypothesize that betahistine dihydrochloride is one of the most important modalities to counter clozapine-associated excessive sedation and the requirement of betahistine dihydrochloride to counter excessive sedation is directly proportional to the dose of clozapine used. No major side effects of betahistine dihydrochloride use were reported. The clozapine-associated sedation and its affinity for the H1 receptor are dose-dependent. Large-scale placebo-controlled trials are needed which aimed to evaluate a dose-dependent effect of betahistine dihydrochloride on sedation. ⁷ In general terms and acknowledging only less number of cases, our findings are in concordance with the previous case report on drugs acting on histaminergic receptors. ⁸ The current case scenarios provide the initial impetus, for further research to explain the role of histamine and its receptor in sleep-wakefulness. In various in vitro studies, H3 receptor antagonists such as thioperamide (10 mg/kg) and carboperamide (20–20 mg/kg) produce dose-dependent and protracted wakefulness with a decrease in non-rapid eye movement sleep and an increase in locomotor activity. The awakening effects of H3 antagonists were prevented by pretreatment with α-methyl-histamine or mepyramine (H3 agonist). The administration of 2-thiazolyl ethylamine (H1-receptor agonist) increased wakefulness, while the administration of pyrilamine (H1 receptor antagonists) blocked the wakefulness-inducing effects of it. Furthermore, pitolisant, a selective H3 receptor antagonist, was recently approved for the management of excessive daytime sleepiness and narcolepsy.^{4, 9} These studies suggest the role of H1 agonists and H3 antagonists in wakefulness. Furthermore, robust studies of these agents on humans for wakefulness are still lacking as there is no replication of this evidence. It is important to research promising therapeutic drugs/molecules that can control drug-associated excessive sedation. The challenges that remain for future studies are to investigate the precise, cellular, and molecular mechanisms of the histaminergic system which leads to wakefulness, and to create specific and selective histamine receptor ligands that can be used to counter drug-associated excessive sedation.

Conclusion

Excessive daytime sedation and drowsiness are the most commonly associated with psychotropic drugs. These side effects can be very troublesome and can lead to significant socio-occupational dysfunction despite no active psychotic symptoms. Besides psychotropic, many other drugs used by physicians (e.g., antihistamines, antiepileptics, muscle relaxants, etc.) also cause excessive sedation. Betahistine dihydrochloride can be a potential option if more scientific data emerge on it, to counter clozapine-associated excessive sedation.

Future challenges include the following:

1. How long betahistine dihydrochloride should continue?

2. Cost–benefit analysis of betahistine dihydrochloride use in such cases.

3. Long-term side effects profile of betahistine dihydrochloride use in such patients.